Reversing the Warburg Effect as a Treatment for Glioblastoma |
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Authors: | Ethan Poteet Gourav Roy Choudhury Ali Winters Wenjun Li Myoung-Gwi Ryou Ran Liu Lin Tang Anuja Ghorpade Yi Wen Fang Yuan Stephen T Keir Hai Yan Darell D Bigner James W Simpkins Shao-Hua Yang |
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Institution: | From the ‡Department of Pharmacology and Neuroscience and ;the §Department of Cell Biology and Anatomy, University of North Texas Health Science Center, Fort Worth, Texas 76107.;the ¶Department of Neurosurgery, Beijing Tiantan Hospital, Beijing Neurosurgical Institute, Capital Medical University, 100050 Beijing, China, and ;the ‖Department of Pathology, Duke University, Medical Center, Durham, North Carolina 27710 |
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Abstract: | Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM. |
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Keywords: | AMP-activated Kinase (AMPK) Bioenergetics Cell Metabolism Energy Metabolism Glioblastoma Tumor Metabolism Methylene Blue Warburg Effect |
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